Citations

Objectives: STAT Mortality Categories (developed 2009) stratify congenital heart surgery procedures into groups of increasing mortality risk to characterize case mix of congenital heart surgery providers. This update of the STAT Mortality Score and Categories is empirically based for all procedures and reflects contemporary outcomes. Methods: Cardiovascular surgical operations in the Society of Thoracic Surgeons Congenital Heart Surgery Database (January 1, 2010 – June 30, 2017) were analyzed. In this STAT 2020 Update of the STAT Mortality Score and Categories, the risk associated with a specific combination of procedures was estimated under the assumption that risk is determined by the highest risk individual component procedure. Operations composed of multiple component procedures were eligible for unique STAT Scores when the statistically estimated mortality risk differed from that of the highest risk component procedure. Bayesian modeling accounted for small denominators. Risk estimates were rescaled to STAT 2020 Scores between 0.1 and 5.0. STAT 2020 Category assignment was designed to minimize within-category variation and maximize between-category variation. Results: Among 161,351 operations at 110 centers (19,090 distinct procedure combinations), 235 types of single or multiple component operations received unique STAT 2020 Scores. Assignment to Categories resulted in the following distribution: STAT 2020 Category 1 includes 59 procedure codes with model-based estimated mortality 0.2% to 1.3%; Category 2 includes 73 procedure codes with mortality estimates 1.4% to 2.9%; Category 3 includes 46 procedure codes with mortality estimates 3.0% to 6.8%; Category 4 includes 37 procedure codes with mortality estimates 6.9% to 13.0%; and Category 5 includes 17 procedure codes with mortality estimates 13.5% to 38.7%. The number of procedure codes with empirically derived Scores has grown by 58% (235 in STAT 2020 vs 148 in STAT 2009). Of the 148 procedure codes with empirically derived Scores in 2009, approximately one-half have changed STAT Category relative to 2009 metrics. The New STAT 2020 Scores and Categories demonstrated good discrimination for predicting mortality in an independent validation sample (July 1, 2017-June 30, 2019; sample size 46,933 operations at 108 centers) with C-statistic = 0.791 for STAT 2020 Score and 0.779 for STAT 2020 Category. Conclusions: The updated STAT metrics reflect contemporary practice and outcomes. New empirically based STAT 2020 Scores and Category designations are assigned to a larger set of procedure codes, while accounting for risk associated with multiple component operations. Updating STAT metrics based on contemporary outcomes facilitates accurate assessment of case mix.

428 Background: Trimodality therapy (TMT) with maximal TURBT followed by chemoradiation(CRT) is a standard of care for select patients with muscle invasive bladder cancer (MIBC). This trial evaluates the activity of atezolizumab (atezo) in MIBC in combination with TMT. This trial was designed with pre-specified safety analyses of the first 80 patients (40 in each arm). At the time of SWOG fall 2020 DSMC report deadline we had enrolled 84 patients but data on only 73 patients were available. The same data are being submitted to ASCO GU meeting. Methods: This trial is testing atezo every 3 weeks for 6 months given concurrently and adjuvantly with CRT vs. CRT alone in 475 patients with MIBC T2-T4aN0M0 disease. Patients are stratified based on PS; T2 vs T3 or T4; choice of chemotherapy; and radiation field (bladder only vs small pelvis). Patients undergo biopsy 3 months after finishing CRT to assess treatment response. Patients are followed for 5 years for recurrence or survival. This trial was not preceded by a phase I study but was designed with a safety run in of 80 patients. Study team agreed on the study design based on available data from other tumor types and initial experience from investigators running smaller similar trials. It was pre-specified that if we observe more than 25% patients having grade 3-5 colitis or cystitis in the atezo arm or any other toxicity which is deemed clinically significant and related to atezo, the trial investigators and DSMC would consider stopping further enrollment. Results: 36 patients were enrolled on the TMT alone arm and 37 patients on the TMT + atezo arm. No grade 3 or higher colitis was reported in the atezo arm. Only one patient had treatment related grade 3 radiation cystitis which was diagnosed after finishing atezo treatment. No steroids were given. Overall 23 grade 3 or higher toxicity events were reported in the atezo arm vs 11 in non- atezo arm. Most common toxicity was hematological which was considered non-immune related. None of the grade 3 or higher toxicities were considered to be immune related by the treating investigator. Conclusions: There is no evidence of increased immune related grade 3-5 AEs.DSMC has recommended to continue enrollment. Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed Clinical trial information: NCT03775265 . [Table: see text]

AbstractParaneoplastic neurological syndrome (PNS) comprises a group of neurological disorders that result from a misguided immune response to the nervous system triggered by a distant tumor. These disorders frequently manifest before the diagnosis of the underlying neoplasm. Since the first reported case in 1888 by Oppenheim, the knowledge in this area has evolved rapidly. Several classic PNS have been described, such as limbic encephalitis, paraneoplastic cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus, sensory neuronopathy, Lambert-Eaton Myasthenic syndrome, and chronic gastrointestinal dysmotility. It is now recognized that PNS can have varied nonclassical manifestations that extend beyond the traditional syndromic descriptions. Multiple onconeural antibodies with high specificity for certain tumor types and neurological phenotypes have been discovered over the past 3 decades. Increasing use of immune checkpoint inhibitors (ICIs) has led to increased recognition of neurologic ICI-related adverse events. Some of these resemble PNS. In this article, we review the clinical, oncologic, and immunopathogenic associations of PNS.

Abstract Introduction Little has been published about the choroidal vascular changes that occur years after radiation exposure. The aim of this study was to review the histological changes observed in the choroidal vasculature following radiotherapy for uveal melanoma. Methods Records from a single institution were retrospectively reviewed from June 7, 2007 to June 7, 2017; 101 patients with a diagnosis of uveal melanoma that underwent enucleation had their records reviewed. Out of these, a total of 26 eyes had undergone plaque brachytherapy prior to enucleation, which had been performed at a mean time of 7.2 years (range from 0 years to 30 years) after the initial plaque placement. A histopathologic analysis was conducted on all 26 eyes with special emphasis on the choroidal changes. Of these 26 eyes, 18 demonstrated evidence of radiation-induced vasculopathy. Results Of the 18 eyes, 10/18 (55%) had radiation retinopathy and 16/18 (89%) had radiation choroidal vasculopathy. One patient had a phthisical eye, and the choroid could not be evaluated because the characteristics of the vasculature could not be determined. Nine cases had vitreous hemorrhage (50%), all cases had radiation retinopathy, and 8/9 (89%) had radiation choroidopathy. Of the 16 cases with radiation choroidal vasculopathy, 3/16 (19%) had only intratumoral radiation choroidal vasculopathy, 3/16 (19%) had only extratumoral radiation choroidal vasculopathy, and, thus, 10/16 (32%) had both intratumoral and extratumoral radiation choroidal vasculopathy. In patients with radiation choroidal vasculopathy, 2/16 (13%) had hyalinization of the choroidal vessels. Another 3/16 (19%) cases with radiation choroidal vasculopathy had ectatic vessels. The other 11/16 (68%) had evidence of both hyalinization of the choroidal vessels as well as ectatic vessels in the choroid. Histological evidence of radiation retinopathy and choroidopathy were seen in 69% of eyes enucleated after receiving radiation therapy, which, in some cases, also had vitreous hemorrhage. Polypoidal choroidal vasculopathy, choroidal neovascularization, and retinal choroidal anastomoses (RAP-type lesions) were seen in 12 of the 16 eyes (75%). Discussion/Conclusion Irradiation of malignant tumors of the eye causes not only radiation retinopathy but also radiation choroidopathy. The role of radiation choroidopathy in the subsequent visual loss following radiotherapy and the role of anti-VEGF therapy needs to be recognized and distinguished from radiation retinopathy. Our data adds to the prior limited knowledge that radiation affects the choroid and can induce specific phenotypes similar to the clinical spectrum of CNV, PCV, and RAP.

Invasive mold infections caused by molds other than Aspergillus spp. or Mucorales are emerging. The reported prevalences of infection due to these rare fungal pathogens vary among geographic regions, driven by differences in climatic conditions, susceptible hosts, and diagnostic capabilities.

AbstractObjectiveNeuroinflammation associated with anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti‐NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)‐1‐mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL‐1 by anakinra, a selective IL‐1 receptor antagonist, blunts antibody‐induced seizures.MethodsWe infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti‐NMDAR encephalitis or monoclonal anti‐NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6‐day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4‐day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium‐binding adapter molecule [Iba]‐1) activation.ResultsOf 31 mice infused with purified patient NMDAR‐IgG (n = 17) or monoclonal NMDAR‐IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody‐induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba‐1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation.SignificanceOur evidence supports a role for IL‐1 in the pathogenesis of seizures in anti‐NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL‐1 receptor‐mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

ObjectiveDuring PREVENT (NCT01892345), eculizumab significantly reduced relapse risk versus placebo in patients with aquaporin‐4 immunoglobulin G‐positive neuromyelitis optica spectrum disorder (AQP4‐IgG+ NMOSD). We report an interim analysis of PREVENT's ongoing open‐label extension (OLE; NCT02003144) evaluating eculizumab's long‐term safety and efficacy.MethodsPatients who completed PREVENT could enroll in the OLE to receive eculizumab (maintenance dose = 1,200 mg/2 weeks, after a blinded induction phase). Safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.ResultsAcross PREVENT and the OLE, 137 patients received eculizumab and were monitored for a median (range) of 133.3 weeks (5.1–276.9 weeks), for a combined total of 362.3 patient‐years (PY). Treatment‐related adverse event (AE) and serious adverse event (SAE) rates were 183.5 in 100 PY and 8.6 in 100 PY, respectively. Serious infection rates were 10.2 in 100 PY in eculizumab‐treated patients versus 15.1 in 100 PY in the PREVENT placebo group. No patient developed a meningococcal infection. At 192 weeks (3.7 years), 94.4% (95% confidence interval [CI], 88.6–97.3) of patients remained adjudicated relapse‐free. The adjudicated annualized relapse rate was 0.025 (95% CI = 0.013–0.048) in all eculizumab‐treated patients versus 0.350 (95% CI = 0.199–0.616) in the PREVENT placebo group. During the OLE, 37% of patients (44 of 119 patients) stopped or decreased background immunosuppressive therapy use.InterpretationThis analysis demonstrates that eculizumab's long‐term safety profile in NMOSD is consistent with its established profile across other indications. This analysis also demonstrated the sustained ability of long‐term eculizumab treatment to reduce relapse risk in patients with AQP4‐IgG+ NMOSD. ANN NEUROL 2021;89:1088–1098

Objective This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). Methods Archival sera from patients with germ cell tumor–associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam‐2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant‐protein Western blot, enzyme‐linked immunosorbent assay (ELISA), and cell‐based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. Results Leucine zipper 4 (LUZP4)–immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28–84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11–IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer‐evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole‐body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T‐cell–dendritic‐cell cocultures from chronic immunosuppression‐naïve LUZP4‐IgG–seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle‐exposed and healthy control cultures. Interpretation LUZP4‐IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen‐specific T‐cell responses support a CD8+ T‐cell–mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001–1010

AbstractTargeted muscle reinnervation enables native muscles to send electromyographic signals to myoelectric receptors, which drive movements in a prosthesis. This system requires voluntary contracture of muscles for sequential control of powered prosthetic joints. This report describes a surgical solution for cases where the chest wall is depleted of muscle targets. A 13‐year‐old boy with left forequarter amputation and pectoralis major resection as a result of extended necrotizing facilities 8 years prior received a neurotized free Vertical Rectus Abdominus Mycocutaneous (VRAM) flap (28 × 10 cm) designed to produce myoelectric signals, reduce pain, and provide stability for prosthetic fitting. Five intercostal nerves from the VRAM were coapted to portions of the brachial plexus to create a myoelectric interface for targeted muscle reinnervation. The postoperative course was uneventful. At 39 months of follow‐up, the patient gained control of the transferred VRAM and was able to operate a custom‐fitted myoelectric prosthesis together with contraction of the ipsilateral infraspinatus muscle. The neurotized VRAM transfer created a neural interface in an area with depleted neuromuscular targets while decreasing pain and adding tissue bulk for proper prosthesis fitting. Such a surgical strategy may have applications in other areas of the body.